IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an alarmin, important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells [and dendritic cells], have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We will examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses. These aims are: Specific Aim 1: Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses. Specific Aim 2: Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.